8GQU

AK-42 inhibitor binding human ClC-2 TMD

8GQU の概要

• エントリーDOI: 10.2210/pdb8gqu/pdb
• EMDBエントリー: 34202
• 分子名称: Chloride channel protein 2, 2-[[2,6-bis(chloranyl)-3-phenylmethoxy-phenyl]amino]pyridine-3-carboxylic acid (2 entities in total)
• 機能のキーワード: homo-dimer, membrane protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 198063.17

構造登録者

Wang, L. (登録日: 2022-08-30, 公開日: 2023-07-05, 最終更新日: 2024-05-08)

主引用文献

Ma, T.,Wang, L.,Chai, A.,Liu, C.,Cui, W.,Yuan, S.,Wing Ngor Au, S.,Sun, L.,Zhang, X.,Zhang, Z.,Lu, J.,Gao, Y.,Wang, P.,Li, Z.,Liang, Y.,Vogel, H.,Wang, Y.T.,Wang, D.,Yan, K.,Zhang, H.
Cryo-EM structures of ClC-2 chloride channel reveal the blocking mechanism of its specific inhibitor AK-42.
Nat Commun, 14:3424-3424, 2023

PubMed Abstract: ClC-2 transports chloride ions across plasma membranes and plays critical roles in cellular homeostasis. Its dysfunction is involved in diseases including leukodystrophy and primary aldosteronism. AK-42 was recently reported as a specific inhibitor of ClC-2. However, experimental structures are still missing to decipher its inhibition mechanism. Here, we present cryo-EM structures of apo ClC-2 and its complex with AK-42, both at 3.5 Å resolution. Residues S162, E205 and Y553 are involved in chloride binding and contribute to the ion selectivity. The side-chain of the gating glutamate E205 occupies the putative central chloride-binding site, indicating that our structure represents a closed state. Structural analysis, molecular dynamics and electrophysiological recordings identify key residues to interact with AK-42. Several AK-42 interacting residues are present in ClC-2 but not in other ClCs, providing a possible explanation for AK-42 specificity. Taken together, our results experimentally reveal the potential inhibition mechanism of ClC-2 inhibitor AK-42.

PubMed: 37296152
DOI: 10.1038/s41467-023-39218-6

実験手法

ELECTRON MICROSCOPY (3.5 Å)